Elongation factor 2 as a novel target for selective inhibition of fungal protein synthesis.
Elongation factor 2 (EF2) is an essential protein catalyzing ribosomal translocation during protein synthesis and is highly conserved in all eukaryotes. It is largely interchangeable in translation systems reconstituted from such divergent organisms as human, wheat, and fungi. We have identified the sordarins as selective inhibitors of fungal protein synthesis acting via a specific interaction with EF2 despite the high degree of amino acid sequence homology exhibited by EF2s from various eukaryotes. In vitro reconstitution assays using purified components from human, yeast, and plant cells demonstrate that sordarin sensitivity is dependent on fungal EF2. Genetic analysis of sordarin-resistant mutants of Saccharomyces cerevisiae shows that resistance to the inhibitor is linked to the genes EFT1 and EFT2 that encode EF2. Sordarin blocks ribosomal translocation by stabilizing the fungal EF2-ribosome complex in a manner similar to that of fusidic acid. The fungal specificity of the sordarins, along with a detailed understanding of its mechanism of action, make EF2 an attractive antifungal target. These findings are of particular significance due to the need for new antifungal agents.
Justice
M C
MC
Department of Basic Animal Science Research, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Hsu
M J
MJ
Tse
B
B
Ku
T
T
Balkovec
J
J
Schmatz
D
D
Nielsen
J
J
D000935:Antifungal Agents / Q000494:pharmacology; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007192:Indenes; D020652:Peptide Elongation Factor 2; D010445:Peptide Elongation Factors / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism*
D000935:Antifungal Agents; D005656:Fungal Proteins; D007192:Indenes; D020652:Peptide Elongation Factor 2; D010445:Peptide Elongation Factors; C003329:sordarin